Acute Hypersensitivity Reactions to Chemotherapy - Case Study Example

Acute Hypersensitivity Reactions to Chemotherapy- Case Study and Discussion Introduction The aim of any antineoplastic therapy, either surgical, radiotherapeutic or pharmacological is complete elimination of all neoplastic cells, and, if this is not possible, atleast to reduce the number of neoplastic cells so that there is improvement in the symptoms, thus prolonging survival and maintaining an adequate quality of life. Since the neoplastic cells are a heterogeneous cellular population with biochemical, morphological and immunological differences, they have varying sensitivity to antineoplastic drugs. All the cells in the same tumor will not be in the same phase in the cell cycle. They usually are either in the proliferative phase or in the rest phase. Also, usually at the time of diagnosis of a tumor, most of the cells would have attained a state of decelerated growth because of poor vascularisation, decreased availability of nutrition as a result of competition and, compression from surrounding cells (Markman, Kennedy & Webster et al, 1999). Most of the available chemotherapeutic drugs are effective on cells that are in their division process. Since most of the tumor cells at the time of chemotherapy are expected to be in a non- division phase, these neoplastic cells will be resistant to the drug. Also, a single drug eliminates only those cells which are sensitive to it and in the long run selects the resistant population. It is due to these reasons that multiple drugs are used for chemotherapy preferably in a successive or phase-associated schedule, keeping in mind the possible kinetic and biochemical changes the tumor cells undergo. Since the action of chemotherapeutic gents is actually not selective to the tumor cells, many considerable side effects can be seen in cell lines expressing higher growth and replication rates. The toxicity may be selective on particular organs mainly the lungs, the liver, the kidneys and the nervous system structures (Markman, Kennedy & Webster et al, 1999). Anaphylaxis reaction is one of the most catastrophic potential complications in oncology. We report the details of a patient who developed hypersensitivity reactions to polysorbate-80 with a history of reaction to either the taxane-moiety or cremaphor EL. Cross-sensitivity between polysorbate-80 and cremophor EL could not be excluded. This case highlights an important aspect in patients experiencing hypersensitivity reactions with chemotherapy administration in an oncology out-patient setting. Not only must consideration be given to the chemotherapy agent but also to the solvent vehicle. Objective To describe a case where assessment of hypersensitivity reactions may be attributable to either the chemotherapy agents or solvent vehicles. Patient characteristics A 66-year-old female with Stage III A Non Small Cell Lung Cancer (NSCLC), was admitted for concurrent platinum-based chemotherapy and radiotherapy. The patient had a history of penicillin hypersensitivity. Initial treatment Carboplatin and paclitaxel is a "gold standard" protocol for good performance status (ECOG 0-2) metastatic NSCLC. The patient initially received carboplatin and paclitaxel, however, developed a severe type 1 hypersensitivity reaction to paclitaxel which responded to prompt, appropriate management. She was not rechallenged. Subsequent Treatment : cisplatin and etoposide Subsequent treatment consisted of cisplatin and etoposide. Due to a world-wide shortage of etoposide phosphate, the patient received intravenous etoposide. The patient was premedicated with intravenous tropisetron 5mg and intravenous dexamethasone 4mg. Within minutes of commencing the infusion the patient complained of shortness of breath and flushing. The infusion was ceased and intravenous hydration, hydrocortisone and promethazine were administered. The patient improved rapidly with complete resolution of symptoms. Alternative Treatment : Cross sensitivity docetaxel and paclitaxel Although there is a 2-5% risk of hypersensitivity with paclitaxel, a commonly used chemotherapeutic agent for various cancers, no formal recommendation exists on the use of taxotere in patients with previous hypersensitivity reactions to other taxanes, including paclitaxel. Alternative treatment with docetaxel was considered. However, potential for reaction to polysorbate-80 solvent, present in both etoposide and docetaxel, was a concern. Cross-sensitivity between paclitaxel and docetaxel, attributable to the taxane-moiety, was also a possibility. Rechallenge : Etoposide Phosphate Fortuitously, etoposide phosphate became available again. Therefore it was decided to rechallenge the patient. The patient was premedicated with hydrocortisone (100mg) and promethazine (25mg) and both etoposide phosphate at an initial dose of 50mg, then 85mg intravenously and cisplatin 75mg intravenously were administered without event. Discussion Hypersensitivity reactions occur as an adverse effect of cancer chemotherapy in up to 40% of patients (Weiss, 1996; O’Brien and Souberbielle, 1992). Carboplatin is considered as one of the well-tolerated cytotoxic agents available currently. It is frequently used both as initial therapy and also second line therapy (Markman, Kennedy & Webster et al, 1999). Several trials have established that a combination of carboplatin with 3 hour infusional paclitaxel has an acceptable toxic profile. Carboplatin by itself has low tendency to develop nephrotoxicity and neurotoxicity (Markman, Kennedy & Webster et al, 1999). Hypersensititivity reaction to carboplatin is rare. Markman, Kennedy & Webster et al (1999) studied hypersensitivity reactions to carboplatin and reported that "Carboplatin hypersensitivity reactions develop in patients who have been extensively pretreated with the agent." Hypersensitivity reactions to carboplatin develop after the patient has received multiple courses of therapy (more than 6) or has received the drug both as a component of initial chemotherapy and in the second-line setting. Many a times the symptoms of hypersensitivity reactions like mild itching or skin rash to this drug may go unnoticed. Also, it is likely that corticosteroids alter the manifestation of symptomatology (Markman, Kennedy & Webster et al, 1999). Both paclitaxel and docetaxel are associated with acute hypersensitivity reactions. The incidence with paclitaxel is approximately 40% (2% severe) and the rate with docetaxel is 30% (7% severe). In early clinical trials, a high incidence of hypersensitivity reactions was observed with paclitaxel with reported fatalities and included: flushing, hemodynamic changes, dyspnea, muscoskeletal pain, paresthesias, and gastrointestinal symptoms. Clinical manifestations include skin changes (pruritis, erythema, rashes, urticaria), angioedema, dyspnea (with or without bronchospasms), blood pressure changes (decrease or increase), and rarely, cardiovascular collapse. Because of poor aqueous solubility, paclitaxel is formulated in cremophor EL (polyoxyethylated castor oil) and ethanol and this substance is thought to be the cause hypersensitivity reactions. Cremophor EL can cause complement C3 activation which can lead to hypersensitivity reactions. Cremophor EL also causes histamine release. Other effects includes Cremophor EL leaching phthalate-type plasticizers from polyvinylchloride (PVC) infusion bags and polyethylene-lined tubing sets, which can result in severe hepatic toxicity. Cremophor EL can also cause peripheral neurotoxicity, possibly because of peroxidation products. This complement activation is concentration-dependent, which explains why slowing the infusion rate can alleviate the hypersensitivity reactions. The incidence of hypersensitivity reactions can be diminished by a preventative protocol of Dexamethasone h1 and H2 blockers, the occurrence of a reaction does not preclude rechallenge with the drug. Allergic reactions have been reported with both cisplatin and its analogue carboplatin. The reactions vary from rashes to urticaria to anaphylaxis. These reactions usually respond promptly to antihistaminics and steroids. Carboplatin is an excellent drug for out patient management. Aggressive rehydration is not necessary with this drug. Since the major route of clearance is renal, it is possible to predict drug exposure based on glomerular filtration rate (Bookman, McGuire, Kilpatrick, et al, 1996). Combination of carboplatin and paclitaxel can be given on out-patient basis. But a combination of cisplatin and paclitaxel should be given only on in-patient basis because paclitaxel has to be delivered over 24 hours (Markman, Kennedy & Webster et al, 1999). When carboplatin is administered with paclitaxel, the reactions to the former may be attributed to the later drug, because, the overall incidence of paclitaxel-associated hypersensitivity reactions appears to be greater than that of carboplatin (Weiss, Donehower, Wiernik, et al, 1990). However, the clinical features of the hypersensitivity help identify the drug which has caused the reaction (table-1). Paclitaxel associated hypersensitivity reactions occur within minutes of initiation of the infusion, and that too during the first course, whereas in case of carboplatin, the reactions occur after multiple courses. The main clinical features in case of paclitaxel are characteristic and include dyspnea, throat tightness, back pain, diffuse erythema, wheezing and hypertension, and these symptoms almost invariably subside after discontinuing the infusion. One more feature about the paclitaxel reactions is that in majority of the patients, once the initial symptoms have settled, it is possible to safely reinitiate the infusion without further development of a second reaction. Carboplatin reactions may occur any time during the infusion but usually are noted at the end of infusion. The features are more severe and may include severe dysnea and diffuse erythema. Other symptoms related to hypersensitivity are generalized pruritus, erythematous rash, facial edema, abdominal cramping, anxiety and tachycardia. In most cases however, despite obvious vasodilatation, hypotension may not be noted. The respiratory distress is attributed to the mucosal edema than bronchospasm (Planner, Weerasiri, Timmins, et al, 1991). Also, the symptoms and signs subside over several hours. Symptoms with a delayed onset such as facial flushing appear not to predict future anaphylaxis and treatment may be continued (Hendrick, Simmons, Cantwell, 1992). It is assumed that during the initial regimens the immune system gets sensitized and then the reactions occur after additional stimulation. Since carboplatin is increasing used in out-patient clinics, oncologists must be aware and expect anaphylactic reactions, especially with multiple courses of therapy (Hendrick, Simmons, Cantwell, 1992). Carboplatin Paclitaxel Initial onset After multiple courses First or second course Onset of symptoms Highly variable (minutes to days) Within minutes of initiation of infusion Symptoms Variable (itching, rash, chest tightness, emesis, blood pressure changes, facial swelling Characteristic (chest tightness, dyspnea, angioedema, back pain, urticaria, blood pressure changes) Ability to safely re-treat Variable (based on severity of symptoms) Almost always Table 1. Differences in Clinical Features Associated With Carboplatin- and Paclitaxel-Induced Hypersensitivity Reactions (Markman, Kennedy & Webster et al, 1999) Markman, Kennedy & Webster et al, 1999, developed a strategy to deal with hypersensitivity reactions to the combination of carboplatin and paclitaxel. First step is to determine if there is any other cause for the symptoms and once this is ruled out, the next step is to assess the severity of the episode. If the reaction is mild, carboplatin may be continued. If the reaction occurs when the patient is in the hospital, diphendramine 50 mg is given intravenously and if the reaction occurs after going home, then the drug is given orally. Carboplatin is continued if there is no worsening of allergic symptoms with subsequent courses. If the reaction is severe, manifesting as dysnea, wheezing and severe erythema, carboplatin may be discontinued until and unless, the drug is very useful to the patient. Alternative medicines to carboplatin include paclitaxel, topotecan, oral etoposide and liposomal doxorubicin. In specific clinical settings, desensitizing the patient or providing maximum immunologic blockade with several days of corticoteroids and prophylactic histamine receptor blockade may be used to help continue the drug further. Patients with severe hypersensitivity to carboplatin may also develop allergy to cisplatin (Weidmann, Mulleneisen, Bojko, et al, 1994 as quoted in Markman, Kennedy & Webster et al, 1999). The podophyllotoxin etoposide has been used clinically for over 30 years in a variety of malignancies. Although intravenous etoposide is generally well tolerated Etoposide has been reported to cause a hypersensitivity reaction in 1-3% of patients (Weiss, 1996). In most patients the reactions occur within the first 5 to 10 minutes of infusion and complete recovery is usual once the infusion is discontinued. Although Hypersensitivity reactions to etoposide are uncommon, they can be life threatening. A well known but rare toxicity is a type I hypersensitivity reaction, manifested by dyspnoea, chest comfort, hypotention, bronchospasm and/or skin flushing. (Weiss 1996: O’Brien and Souberbielle,1992). Possible mechanisms involve histamine release, release of oleic acid; a fatty acid which interferes with malignant cell proliferation from the inhibition of angiogenesis and formation of peroxides. Oleic acid may also be a cause of hypersensitivity reactions. Ethanol, benzyl alcohol, polyethylene glycol may be responsible for the cardiovascular, neurological and/or respiratory side effects. Fortunately, most reactions subside quickly when the infusion is stopped and serious consequences are uncommon. It remains unclear whether this reaction is due to either the active drug or the solvent (Weiss 1996). The subsequent management of patients experiencing a HSR to etoposide was usually the omission of etoposide from the chemotherapy regimen (Athanassiou et al 1988; De Souza et al 1994 Tucci and Pirtoli, 1985 Donegan, 1989). Features that indicate that this reaction is not immunologically mediated include: no relationship to the first or repeat doses, no reported cases with oral etoposide, lower risk when drug given by central lines and successful rechallenge usually possible. However, it is well established that, where subsequent doses of etoposide are deemed necessary, replacement with etoposide phosphate is a reasonable and viable alternative. (Siderov 2002). Peereboom et al (1993) reported that retreatment with taxol after major hypersensitive reactions is feasible using multiple high doses of corticosteroids and antihistamine premedications and a reduced taxol infusion rate under close supervision. Unlike platinum compounds, retreatment with etoposide in cases of hypersensitivity is difficult. Many studies have proven the usefulness of etoposide phosphate in such cases. Collier et al, 2008 studied 6 cases of etoposide hypersensitivity. They reported that etoposide phosphate could be safely used in these patients and that treatment with etoposide phosphate proceeded without any symptoms or the use of repeated steroid cover in 5 of the 6 patients. Formulations of etoposide phosphate do not contain polysorbate 80 and there have been no case reports in the literature of hypersensitivity reactions to etoposide phosphate. In addition the fact that no reports of hypersensitivity reactions caused by oral etoposide, a formulation containing citric acid, glycerin and polyethylene glycol, but no polysorbate 80, provides additional support for our conclusion. Therefore the substitution of etoposide phosphate in patients who experience a hypersensitivity reaction to etoposide rather than rechallenge would seem appropriate. There have been case reports of successful rechallange with etoposide phosphate however this case highlights the complexity of patients with multiple hypersensitivities associated with different formulations and raises the possibility of cross sensitivity between Cremophor EL and polysorbate-80. Formulation Active Ingredient Excipients Taxol Paclitaxel Cremaphor EL and ethanol Taxotere Docetaxel Polysorbate-80 and ethanol Etoposide Etoposide Polysorbate-80 and Ethanol, Benzyl alcohol, Polythylene glycol Etoposide Etoposide No excipients Conclusion In this case, despite experiencing a hypersensitivity reaction to intravenous etoposide, subsequent administration of intravenous etoposide phosphate was well tolerated without any allergic sequelae. It was concluded that the hypersensitivity reaction was attributable to polysorbate-80 Polysorbate-80 and ethanol, the formulation vehicles for etoposide and docetaxel, have been responsible for acute hypersensitivity reactions. Similarly, paclitaxel is formulated in the nonionic surfactant cremophor EL and ethanol. This vehicle has been associated with acute hypersensitivity reactions. This patient has a hypersensitivity to either the taxane-moiety or cremaphor EL. Cross-sensitivity between polysorbate-80 and cremophor EL should not be excluded. This case highlights a patient with a hypersensitivity to polysorbate-80 with a history of reaction to either the taxane-moiety or cremaphor EL. Cross-sensitivity between polysorbate-80 and cremophor EL could not be excluded. References Athanassiou, A.E., Bafaloukas, D., Pectasidis, D., Dimitriadis, M., 1988. Acute vasomotor response – a reaction to etoposide. J Clin Oncol, 6, 602-603 (letter) Bookman, M.A., McGuire, W.P., Kilpatrick, D., et al, 1996. Carboplatin and paclitaxel in ovarian carcinoma: A phase I study of the Gynecologic Oncology Group. J Clin Oncol., 14, 1895-1902, 1996. Collier, K., Schink, C., Young, A. M., How, K., Seckl, M., & Savage, P., 2008. Successful treatment with etoposide phosphate in patients with previous etoposide hypersensitivity. Journal of Oncology Pharmacy Practice, 14 (1), 51-55. De Souza, P., Friedlander, M., Wilde, C., Kristen, F., Ryan, M. 1994. Hypersensitivity reactions to etoposide. Am J Clin Oncol., 17, 387-389. Donegan, S., 1989. An unusual reaction to etoposide. Drug Intell Clin Pharm, 23, 177: (letter) Friedland, D., Gorman, G.,Ttreat, J., 1993. Hypersensitivity reactions from taxol and etoposide. Journal of the National Cancer Institute, 85, 2036. Hendrick, A.M., Simmons, D., Cantwell, B.M.J., 1992. Allergic reactions to carboplatin. Ann Oncol., 3, 239-240. Markman, M., Kennedy, A., Webster, K., Elson, P., Peterson, G., Kulp, B., & Belinson, J., 1999. Clinical Features of Hypersensitivity Reactions to Carboplatin. Journal of Clinical Oncology, 17 (4), 1141 O’Brien, M.E.R., Souberbielle, B.E., 1992. Allergic reactions to cytotoxic drugs- an update. Annals Oncol., 605-610. Peereboom, D.M., Donehower, R.C., Eisenhauer, E.A., et al, 1993. Successful re-treatment with Taxol after major hypersensitivity reactions. J Clin Oncol., 11, 885-890. Planner, R.S., Weerasiri, T., Timmins, D., et al, 1991. 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